Macrophage‐Derived Nanosponges Adsorb Cytokines and Modulate Macrophage Polarization for Renal Cell Carcinoma Immunotherapy

Abstract

AbstractRenal cell carcinoma (RCC) is a hot tumor infiltrated by large numbers of CD8+ T cells and is highly sensitive to immunotherapy. However, tumor‐associated macrophages (TAMs), mainly M2 macrophages, tend to undermine the efficacy of immunotherapy and promote the progression of RCC. Here, macrophage‐derived nanosponges are fabricated by M2 macrophage membrane‐coated poly（lactic‐co‐glycolic acid）（PLGA）, which could chemotaxis to the CXC and CC chemokine subfamily‐enriched RCC microenvironment via corresponding membrane chemokine receptors. Subsequently, the nanosponges act like cytokine decoys to adsorb and neutralize broad‐spectrum immunosuppressive cytokines such as colony stimulating factor‐1(CSF‐1), transforming growth factor‐β（TGF‐β）, and Lnterleukin‐10（IL‐10）, thereby reversing the polarization of M2‐TAMs toward the pro‐inflammatory M1 phenotype, and enhancing the anti‐tumor effect of CD8+ T cells. To further enhance the polarization reprogramming efficiency of TAMs, DSPE‐PEG‐M2pep is conjugated on the surface of macrophage‐derived nanosponges for specific recognition of M2‐TAMs, and the toll like receptors 7/8（TLR7/8） agonist, R848, is encapsulated in these nanosponges to induce M1 polarization, which result in significant efficacy against RCC. In addition, these nanosponges exhibit undetectable biotoxicity, making them suitable for clinical applications. In summary, a promising and facile strategy is provided for immunomodulatory therapies, which are expected to be used in the treatment of tumors, autoimmune diseases, and inflammatory diseases.